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Algorithm for neuropathic pain treatment: An evidence based proposal
N.B. Finnerupa,*, M. Ottob,1, H.J. McQuayc,2, T.S. Jensena,3, S.H. Sindrupb,4
a
Department of Neurology, Danish Pain Research Centre, Aarhus University Hospital, Aarhus Sygehus, Noerrebrogade 44, Aarhus 8000, Denmark
b
Department of Neurology, Odense University Hospital, Sdr. Boulevard 29, Odense 5000, Denmark
c
Pain Relief Unit, Churchill Hospital, Oxford OX3 7LJ, UK
Received 5 May 2005; received in revised form 14 July 2005; accepted 8 August 2005
Abstract
New studies of the treatment of neuropathic pain have increased the need for an updated review of randomized, double-blind, placebo-
controlled trials to support an evidence based algorithm to treat neuropathic pain conditions. Available studies were identified using a
MEDLINE and EMBASE search. One hundred and five studies were included. Numbers needed to treat (NNT) and numbers needed to harm
(NNH) were used to compare efficacy and safety of the treatments in different neuropathic pain syndromes. The quality of each trial was
assessed. Tricyclic antidepressants and the anticonvulsants gabapentin and pregabalin were the most frequently studied drug classes. In
peripheral neuropathic pain, the lowest NNT was for tricyclic antidepressants, followed by opioids and the anticonvulsants gabapentin and
pregabalin. For central neuropathic pain there is limited data. NNT and NNH are currently the best way to assess relative efficacy and safety,
but the need for dichotomous data, which may have to be estimated retrospectively for old trials, and the methodological complexity of
pooling data from small cross-over and large parallel group trials, remain as limitations.
q 2005 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
0304-3959/$20.00 q 2005 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.pain.2005.08.013
290 N.B. Finnerup et al. / Pain 118 (2005) 289–305
However, these reviews need to be updated because of the The outcome of a trial (positive or negative) was judged by
publication of new trials, and the limitations of the NNT and the reviewers in those cases where authors’ conclusions were
NNH approach need to be discussed. This paper provides at odds with the change in the primary outcome measure.
up-to-date calculations of NNT and NNH in neuropathic Heterogeneity was examined visually using L’Abbé plots
(L’Abbé et al., 1987). An instrument suggested by Jadad et al.
pain as the basis of a proposal for an evidence-based
(1996) was used as a measure of quality. Validity tests (e.g. Smith
treatment algorithm.
et al., 2000) were not used.
2. Methods
3. Results
2.1. Search strategy
Full reports of randomized placebo-controlled double-blind 3.1. Study and patients characteristics of included trials
studies published in peer-reviewed journals were identified using
free-text searches of MEDLINE (1966–April 2005), EMBASE Eligible randomized placebo-controlled trials with
(1974–April 2005), Cochrane Review, and Cochrane CENTRAL. references, study characteristics, and quality score are
Each drug was only searched by one author. Additional papers provided in Table 2. One hundred and five randomized,
were identified from previous published reviews and reference lists double-blind, placebo-controlled studies that met the
of retrieved papers. Letters were sent to corresponding authors of inclusion and exclusion criteria were included. Fifty-
papers that did not provide dichotomous data to ask if they could nine used a cross-over and 46 a parallel design. Five
provide us with such data.
studies used an active placebo. Twenty-six trials
examined antidepressants (21 cross-over and five
parallel design), 39 anticonvulsants (18 cross-over and
2.2. Selection criteria 21 parallel design), 11 examined opioids, seven NMDA
antagonists, nine mexiletine, four topical lidocaine,
Randomized double-blind studies in neuropathic pain con-
three cannabinoids, 11 capsaicin, and one a glycine
ditions using chronic dosing and placebo studying at least 10
patients were included. Studies not written in English were
antagonist. The trials included patients with central
excluded. Studies on cancer neuropathic pain were also excluded post-stroke pain, spinal cord injury pain, multiple
except for well-defined post-mastectomy pain syndromes and post- sclerosis, painful polyneuropathy, post-herpetic neural-
surgical pain with post-operative pain compatible with a nerve gia, phantom limb pain, post-mastectomy and post-
section. surgical pain, brachial plexus avulsion, trigeminal
neuralgia, HIV-neuropathy, and mixed neuropathic
pain conditions. The trials are discussed below by
2.3. Data abstraction, quality assessment, and drug class.
quantitative data synthesis
(balanced TCA NNT: 2.5 (1.8–3.9) vs noradrenergic TCA mixed neuropathic pain states, post-herpetic neuralgia,
NNT: 3.1 (2.2–5.5)). painful diabetic neuropathy, and spinal cord injury. The
The selective serotonin reuptake inhibitors (SSRIs) and overall NNT for gabapentin in neuropathic pain, including
the mixed serotonin noradrenaline reuptake inhibitors all conditions, high as well as low doses, is 5.1 (4.1–6.8),
(SNRIs) have been adequately tested in painful polyneuro- but by excluding the study using only 900 mg/day, the
pathy. For SSRIs, the overall NNT is nearly 7 and one of the study on mixed neuropathic pain, and including only the
three trials did not find better effect with active than high dose of 2400 mg in Rice and Maton (2001), the
placebo. The SNRI venlafaxine has an NNT in painful combined NNT is 3.8 (3.1–5.1). The NNH for withdrawal
polyneuropathies of around 4. Bupropion, a noradrenaline for gabapentin is 26.1 (14.1–170). One small crossover
and dopamine reuptake inhibitor, was reported-in a small study (19 completed patients) compared gabapentin (up to
trial of 41 patients—to relieve pain in a group of patients 1800 mg) with amitriptyline (up to 75 mg) in painful
with neuropathic pain of different etiologies. diabetic neuropathy (Morello et al., 1999). There was no
The NNH is 14.7 (10.2–25.2) for TCA, and for SNRI significant difference in pain scores during gabapentin and
and SSRI the relative risk for trial withdrawal is not amitriptyline treatment, pain intensity score change from
significant. baseline, and global ratings of pain relief (52% with at least
moderate pain relief during gabapentin and 67% during
3.3. Anticonvulsants amitriptyline) (PO0.1). Both treatments caused similar
rates of adverse events. Post hoc analysis revealed that a
The early trials on carbamazepine do not meet current sample size of approximately 260 patients is necessary to
methodological standards (e.g. use of validated outcome provide 80% power to detect a mean difference of one third
measures, sample size calculation, and adequate description of the difference between mild and moderate pain at a 0.05
of randomization procedure, statistical methods, and patient significance level.
flow), but an attempt to calculate NNT gives a combined The efficacy of gabapentin in combination with
NNT in trigeminal neuralgia of 1.7 (1.3–2.2). In painful venlafaxine was studied in painful diabetic neuropathy
diabetic neuropathy, the NNT from one trial with 30 patients
(Simpson, 2001). In the second part of the study including
on 200–600 mg daily was 2.3 (1.6–3.9) and in post-stroke
12 patients who did not respond to gabapentin, gabapentin
pain there was a small but not statistically significant effect
plus venlafaxine improved pain and quality of life compared
of 800 mg daily with a NNT of 3.4 (1.7–105). The combined
with gabapentin plus placebo. In another study, the
NNH for carbamazepine in neuropathic pain is 21.7 (12.6–
combination of gabapentin and morphine was superior to
78.5), based on a total of 152 patients. Randomized
gabapentin alone, morphine alone and the active placebo
controlled trials comparing oxcarbazepine to carbamaze-
lorazepam in patients with post-herpetic neuralgia or painful
pine have reported comparable analgesic effect between the
diabetic neuropathy (Gilron et al., 2005).
two treatments with fewer side effects during oxcarbazepine
Pregabalin in post-herpetic neuralgia and painful diabetic
(for review, see Beydoun and Kutluay (2002), Carrazana
and Mikoshiba (2003)), but these trials have not yet been neuropathy has a combined NNT for doses ranging from
published fully. 150 to 600 mg of 4.2 (3.4–5.4), comparable to the effect of
Phenytoin had a positive effect on painful diabetic gabapentin. The NNH for withdrawal was 11.7 (8.3–19.9)
neuropathy in one trial (NNT: 2.1 (1.5–3.6)), while another indicating a relatively high withdrawal rate (see Section 4).
showed no analgesic effect. In patients with acute flare-ups Lamotrigine up to 400 mg daily has a pain relieving
of various neuropathic pain conditions intravenous pheny- effect in trigeminal neuralgia as an add-on treatment (NNT:
toin 15 mg/kg over 2 h had a significant pain-relieving effect 2.1 (1.3–6.1)), in painful diabetic neuropathy (NNT: 4.0
(McCleane, 1999a). (2.1–42)), and in central post-stroke pain. In HIV-associated
Valproate in three parallel group trials from the same painful sensory neuropathy, a small study showed a
centre with 43–57 patients had high efficacy in relieving significant effect of lamotrigine 300 mg daily, but an
pain in painful diabetic neuropathy and post-herpetic extended larger study using 600 mg daily only demonstrated
neuralgia in doses up to 1200 mg with very low NNTs, an effect on some secondary parameters in those patients
while a crossover trial of 31 patients from another centre receiving neurotoxic antiretroviral therapy. In spinal cord
found no difference between valproate 1500 mg and placebo injury pain lamotrigine had no effect, although it had an
in treating painful polyneuropathy and also showed no effect effect on spontaneous pain in a subgroup of patients with
in the subgroup of patients with diabetic neuropathy. incomplete injury and evoked pain.
Valproate in doses up to 2400 mg/day was not significantly Topiramate in doses up to 400 mg failed to relieve pain
better than placebo in relieving pain in patients with spinal in three large trials including in total 1259 patients with
cord injuries. painful diabetic neuropathy, while another trial found a
Gabapentin has been studied in several large trials and significant effect (NNT: 7.4 (4.3–28.5)). The four topir-
has a documented moderate effect on pain and quality of amate studies had a high withdrawal rate due to side effects
life measures including mood and sleep disturbance in (NNH: 6.3 (5.1–8.1)).
292 N.B. Finnerup et al. / Pain 118 (2005) 289–305
Neuropathic Central pain Peripheral pain Painful poly- Post-herpetic Peripheral Trigeminal HIV neuropa- Mixed neuro- NNH in neu-
paina neuropathy neuralgia nerve injury neuralgia thy pathic pain ropathic pain
Antidepressants
TCA 3.1 (2.7–3.7) 4.0 (2.6–8.5) 2.3 (2.1–2.7) 2.1 (1.9–2.6) 2.8 (2.2–3.8) 2.5 (1.4–11) ND ns NA 14.7 (10–25)
SSRI 6.8 (3.4–441) ND 6.8 (3.4–441) 6.8 (3.4–441) ND ND ND ND ND ns
SNRI 5.5 (3.4–14) ND 5.5 (3.4–14) 5.5 (3.4–14) ND NA ND ND ND ns
DNRI 1.6 (1.3–2.1) ND ND ND ND ND ND ND 1.6 (1.3-2.1) ns
Antidepressants 3.3 (2.9–3.8) 4.0 (2.6–8.5) 3.1 (2.7–3.7) 3.3 (2.7–4.1) 2.8 (2.2–3.8) 2.5 (1.4–11) ND ns 1.6 (1.3–2.1) 16.0 (12–25)
NNH, combined numbers needed to harm (95% confidence interval) to obtain one patients to withdraw because of side effects. TCA, tricyclic antidepressants; SNRI, serotonin noradrenaline reuptake inhibitors;
SSRI, selective serotonin reuptake inhibitors; DNRI, dopamine noradrenaline reuptake inhibitors; ND, no studies done; NA, dichotomized data are not available; ns, relative risk not significant.
a
Heterogeneity across different pain conditions.
293
294 N.B. Finnerup et al. / Pain 118 (2005) 289–305
Fig. 1. Numbers needed to treat in peripheral and central neuropathic pain. Combined numbers needed to treat (NNT) to obtain one patient with more than 50%
pain in (a) peripheral neuropathic pain (painful polyneuropathy, postherpetic neuralgia, and peripheral nerve injury pain) and (b) central pain (central post-
stroke pain, pain following spinal cord injury and multiple sclerosis). SNRI, serotonin noradrenaline reuptake inhibitors; SSRI, selective serotonin reuptake
inhibitor. Circle size and related numbers indicate number of patients who have received active treatment. *At least half of conducted trials showed no
significant effect.
larger parallel group trials. The differences in NNT values treatment efficacy for different drugs as evidenced by NNT
based on the intention-to-treat population as opposed to the values which varied from 1.2 to non-significant relative
completed population can be estimated by calculating NNTs risks. The question is whether the NNT method permits
in studies with a parallel group design and comparing it with generation of a treatment algorithm for neuropathic pain.
the NNT using the completed population. This is, however, The NNT method for comparing drugs can be criticized
not possible based on the reports, as most studies carry for various reasons:
forward the pain ratings for patients who do not complete
the study, and use these data in the analysis. But based on 1. The relative efficacy and safety is derived from placebo
the ‘worst case’, i.e. assuming that all patients withdrawn comparisons of each active drug. Trials which do not
are non-responders, the NNT for pregabalin based on the compare with placebo are therefore excluded.
completed population is 3.4 (2.7–4.3) compared with 4.2 2. Calculation of NNT is done retrospectively from
(3.4–5.4) based on the intention-to-treat population. studies with different cut-off points for defining pain
relief.
3. Pain relief per se may be a crude measure, which does
4. Discussion not take other specific measures into account like
impact on daily living and quality of life.
4.1. Numbers needed to treat and harm 4. Use of different inclusion and exclusion criteria makes
it difficult to compare and to combine studies.
This meta-analysis using numbers needed to treat (NNT) 5. NNT values cannot be calculated when conversion to
shows that it is possible to distinguish pharmacological dichotomous data is not possible.
N.B. Finnerup et al. / Pain 118 (2005) 289–305 295
6. As for all meta-analyses there is a risk that NNT However, a recent trial showed an NNT of 4.2 (2.7–9.4)
values will overestimate the efficacy if negative trials without excluding gabapentin non-responders (Richter
are not published. et al., 2005).
Combining cross-over and parallel designed studies in
The advantage of using NNTs is that they provide a meta-analyses is another concern (Elbourne et al., 2002),
clinically meaningful measure of effect and risk of each and the generally lower NNT value with the tricyclic
drug, and data from different trials, even with different antidepressants may in part be due to the fact that 19/23
outcome measures, can be pooled. The legitimacy of the trials were cross-over trials compared to 2/12 of the
pooling depends on similar therapeutic context, patients, gabapentin/pregabalin trials.
duration of study, and clinical homogeneity. Selection bias may be present and includes publication
It is important to bear in mind that some of these NNT bias, which arises from higher tendency for studies with a
values in neuropathic pain are obtained from studies of statistically significant effect of treatment to be published
variable quality and most available studies are short-term thereby introducing bias in meta-analyses (Moher et al.,
studies with no information on long-term effect. 1999). We have no direct evidence that this problem applies
The choice of a 33 or 50% cutoff when calculating NNTs to this data set, and indeed there are a number of negative
has little impact on NNT values because efficacy of both studies included in the analysis.
active and placebo treatments changes (McQuay and
Moore, 1998).
4.4. Treatment algorithm
In the present analysis, calculation of NNH was based on
patients that withdrew from the study because of adverse
Based on the available randomized clinical trials, it is of
effects, and we have not included other side-effects that may
interest to see if an evidence-based approach for managing
be bothersome for long-term treatment, e.g. constipation
neuropathic pain is possible. In choice of treatment for
and dizziness. The design itself may influence the NNH
neuropathic pain a set of different criteria are relevant
value. A compound with a high NNH value from a short
including:
lasting trial may still be unsuitable for long-term use. An
example is chronic phenytoin treatment causing gingival 1. Consistent outcome in high-quality randomized con-
hyperplasia, hirsutism, polyneuropathy and hepatotoxicity trolled trials.
(Rogvi-Hansen and Gram, 1995). Compounds may also 2. High degree of pain relief and superiority to existing
cause serious side effects not reflected in the NNH value, treatments.
e.g. sudden death associated with TCA (Ray et al., 2004) or 3. Persistent pain relieving effect.
Stevens-Johnson syndrome after treatment with lamotrigine 4. Few and only mild side effects.
(Mackay et al., 1997). 5. Effect on quality of life.
6. Low cost.
4.2. Quality of randomized controlled trials
Because of heterogeneity across treatment of different
Quality of trials varies for obvious reasons and the pain conditions, algorithms need to be tailored to specific
variation in quality may lead to bias in meta-analyses diseases or disease categories.
(Alderson et al., 2003; Detsky et al., 1992; Moher et al., There are no existing data which permit generation of an
1999) and existing criteria have their limitations. It is algorithm based on a combination of all the above criteria
possible that we had obtained other results if more stringent mainly because of a lack of comparative studies between
quality and validity criteria were used (Detsky et al., 1992; existing and new compounds using the same set of primary
Smith et al., 2000). and secondary endpoints.
A treatment algorithm for peripheral neuropathic pain
4.3. Heterogeneity and selection bias (painful neuropathy, painful diabetic neuropathy, post-
herpetic neuralgia and peripheral nerve injury pain) is
The major cause of heterogeneity was dose, pain described below. The algorithm deals only with pharmaco-
diagnosis, and study design, with small, cross-over trials logical considerations. Needless to say for all pain
having the lowest NNT values. There was also a large conditions, non-pharmacological treatments should be
variation in placebo response among studies. considered. The algorithm can be described in a hierarchical
Some of the studies on gabapentin and pregabalin fashion in which increasing numbers of criteria are taking
excluded patients who failed to respond to previous into account:
treatment with gabapentin, which may bias efficacy If only one set of criteria: pain relief is used then the list
comparisons with other drugs using NNT values. Calculat- of drugs for neuropathic pain look like this: TCAO
ing the impact of this enriched enrolment on the overall opioidsRtramadolRgabapentin/pregabalin.
NNT, taking the worst case scenarios, the NNT for If the criteria for efficacy are based on both pain relief
pregabalin is 5.4 (4.3–7.1) compared to 4.2 (3.4–5.4). and quality of life measures then such data are not existent
296 N.B. Finnerup et al. / Pain 118 (2005) 289–305
for several of the old compounds such as TCA, carbama- In trigeminal neuralgia, carbamazepine is suggested as
zepine, and phenytoin and the list is likely to look as first choice because of consistent outcome with a low NNT,
follows: gabapentin/pregabalinOtramadolOopioidsO although in studies of varying quality. Oxcarbazepine (as
TCA. yet no published trials) may be an alternative.
If additional requirements such as side effects and study In central pain few studies exist and it is unknown
design are taken into account then important and occasion- whether an effective treatment in one central pain condition
ally dangerous side effects of TCA and strong opioids need can be expected to be effective in other central pain
to be considered. Under these conditions the algorithm for conditions. Therefore, a treatment algorithm in these pain
peripheral neuropathic pain may be as shown in Fig. 2. The conditions needs to be based partly on the experience in
effect of gabapentin and TCAs are documented in large and peripheral neuropathic pain conditions, until further studies
numerous trials with good quality and with consistent arise. TCAs are often not tolerated in the elderly patients
outcomes. One small trial compared gabapentin and with stroke, so, in these cases, gabapentin/pregabalin seems
amitriptyline and found no difference in pain scores to be first choice. TCAs, lamotrigine, cannabinoids,
(Morello et al., 1999). TCAs have lower NNT values than tramadol, and opioids may be second choice.
gabapentin/pregabalin but as discussed above part of this For future trials, we encourage authors to:
difference may be due to differences in study design.
Furthermore, as gabapentin/pregabalin have higher NNH (1) report the trial to a central database (DeAngelis et al.,
values and lack serious adverse effects it thus seems 2004);
reasonable to have these two drug classes as first line (2) to follow Good Clinical Practice (GCP) requirements
treatment of peripheral neuropathic pain. As new studies on (ICH, 1997; Jorgensen et al., 2004);
SNRIs (with fewer side effects than TCAs) are emerging, (3) to follow the guidelines in the consort statement (Moher
these drugs may replace TCAs. Tramadol and oxycodone et al., 2001);
may be considered second or third line drugs. The NNT (4) to do more head-to head comparisons.
values are for these and other opioids low, and a direct
comparison study show equal or slightly better effect of The relative efficacy rank order obtained by the NNT
morphine compared to gabapentin (Gilron et al., 2005). method agree to some extent with the few head-to-head
Anxieties about dependence, cognitive impairment, and comparisons performed in neuropathic pain (Gilron et al.,
tolerance issues, although there is no hard evidence for such 2005; Morello et al., 1999; Raja et al., 2002; Sindrup et al.,
problems, may make opioids a less attractive choice. 2003), but to look for subtle differences head-to-head
Combination of drugs targeting separate mechanisms comparisons are needed. Furthermore, it may be inappropri-
theoretically may improve treatment, but, except for the ate to use of placebo in severe pain, for instance in
combination of gabapentin with venlafaxine or morphine, trigeminal neuralgia, making it difficult to obtain relative
evidence for this is still lacking. efficacy estimates based on placebo comparisons. This
Peripheral neuropathic
pain
Lidocaine patch*
yes
TCA contraindication
no
Gabapentin/ TCA
pregabalin (SNRI)
yes
TCA contraindication
no
TCA Gabapentin/
(SNRI) pregabalin
Tramadol, oxycodone
Fig. 2. Treatment algorithm. Proposed algorithm for the treatment of peripheral neuropathic pain. TCA, tricyclic antidepressants; SNRI, serotonin
noradrenaline reuptake inhibitors. *Pain relieving effect of topical lidocaine has been shown in patients with allodynia.
Table 2
Randomized, double-blind, placebo-controlled trials of different drugs in various neuropathic pain conditions
Active drug daily drug dose Study quality rating Design patient Outcome Pain relief NNT (95% CI) Drop outs side effects NNH (95% CI)
nos
Active Placebo Active Placebo
Antidepressants
Central post-stroke pain
Amitriptyline, 75 mg Leijon and Boivie, 1989, 4 Cross-over, 15 AmiOpla 10/15 1/14 1.7 (1.2–3.1) 0/15 0/15 ns
Spinal cord injury pain
Amitriptyline, average 50 mg Cardenas et al., 2002, 4 Parallel, 84 AmiZpla 8/44 2/40 ns 7/44 2/40 ns
Painful polyneuropathy
Imipramine, 100 mg Kvinesdal et al., 1984, 4 Cross-over, 12 ImiOpla 7/12 0/12 1.7 (1.2–3.3) 1/13 0/13 ns
Nortriptyline, 30 mg Gomez-Perez et al., 1985, 4 Cross-over, 18 NorOpla 16/18 1/18 1.2 (1.0–1.5) 0/18 0/18 ns
Amitriptyline, average 90 mg Max et al., 1987, 4 Cross-over, 29 AmiOpla 15/29 1/29 2.1 (1.5–3.5) 3/32 2/31 ns
a
Imipramine, average 200 mg Sindrup et al., 1990a, 4 Cross-over, 20 ImiOpla 17/19 3/20 1.3 (1.0–1.9) 7/29 0/20 4.1 (2.5–11.7)
a
Clomipramine, 75 mg Sindrup et al., 1990b, 4 Cross-over, 19 CloOpla 10/19 1/19 2.1 (1.4–4.4) 3/24 0/20 ns
a
Desipramine, 200 mg Sindrup et al., 1990b, 4 Cross-over, 19 DesOpla 7/19 1/19 3.2 (1.8–13.0) 3/23 0/20 ns
297
(continued on next page)
298
Table 2 (continued)
Active drug daily drug dose Study quality rating Design patient Outcome Pain relief NNT (95% CI) Drop outs side effects NNH (95% CI)
nos
Active Placebo Active Placebo
Anticonvulsants
Central post-stroke pain
Carbamazepine, 800 mg Leijon and Boivie, 1989, 4 Cross-over, 15 CarbZpla 5/14 1/15 3.4 (1.7–105) 1/15 0/15 ns
Lamotrigine, 200 mg Vestergaard et al., 2001, 5 Crossover, 30 LtgOpla NA NA NA 3/30 0/27 ns
Spinal cord injury pain
Lamotrigine, 200–400 mg Finnerup et al., 2002, 5 Crossover, 22 LtgZpla 4/21 4/21 ns 1/27 2/28 ns
Valproate, 600–2400 mg Drewes et al., 1994, 3 Crossover, 20 ValZpla 6/20 4/20 ns 0/20 0/20 ns
Gabapentin, up to 3600 mg Levendoglu et al., 2004, 4 Crossover, 20 GabOpla NA NA NA 0/20 0/20 ns
Painful polyneuropathy
cd
Carbamazepine, 200–600 mg Rull et al., 1969, 2 Crossover, 30 CarbOpla 26/42 8/45 2.3 (1.6–3.9) 2/30 0/30 ns
c
Carbamazepine, 600 mg Wilton, 1974, 3 Crossover, 40 CarbOpla NA NA NA NA NA NA
c
Phenytoin, 300 mg Saudek et al.1977, 2 Crossover, 12 PheZpla NA NA NA 2/12 0/12 ns
299
300
Table 2 (continued)
Active drug daily drug dose Study quality rating Design patient Outcome Pain relief NNT (95% CI) Drop outs side effects NNH (95% CI)
nos
Active Placebo Active Placebo
Peripheral nerve injury
Mexiletine, 750 mg Chabal et al., 1992, 3 Cross-over, 11 MexOpla 6/11 1/11 2.2 (1.3–8.7) 0/11 0/11 ns
HIV-neuropathy
Mexiletine, up to 600mg Kieburtz et al., 1998, 5 Parallel, 98 MexZpla 22/48 24/50 ns 4/48 1/50 ns
Mexiletine, up to 600 mg Kemper et al., 1998, 3 Cross-over, 16 MexZpla NA NA NA 2/22 9/22 ns
Mixed patients
bo
Mexiletine, 900 mg Wallace et al., 2000, 3 Cross-over, 20 MexZpla NA NA NA 0/20 0/20 ns
Topical lidocaine
Postherpetic neuralgia
o
Lidocaine gel, 5% Rowbotham et al., 1995, 4 Cross-over, 39 LidOpla NA NA NA 1/46 2/46 ns
o
Lidocaine patch, 5% Rowbotham et al., 1996, 4 Cross-over, 35 LidOpla NA NA NA 0/35 0/35 ns
HIV-neuropathy
PlaZplacebo, sublZsublingual, NA: dichotomized data are not available, ns: relative risk not significant.
a
Additional data provided by author.
b
Study include questionable neuropathic pain conditions.
c
Data limited and difficult to interpret.
d
30 patients on multiple cross-over.
e
900 mg/day of gabapentin may be too low a dose for achieving an analgesic effect.
f
Patients failing to respond to pre-study gabapentin excluded, which may cause an overestimation of the efficacy of pregabalin and gabapentin.
301
302 N.B. Finnerup et al. / Pain 118 (2005) 289–305
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